Air enema reduction versus hydrostatic enema reduction for intussusceptions in children: A systematic review and meta-analysis

Objectives We conducted a comprehensive meta-analysis to compare the effectiveness and safety of fluoroscopy-guided air enema reduction (FGAR) and ultrasound-guided hydrostatic enema reduction (UGHR) for the treatment of intussusception in pediatric patients. Methods A systematic review and meta-analysis were conducted on retrospective studies obtained from various databases, including PUBMED, MEDLINE, Cochrane, Google Scholar, China National Knowledge Infrastructure (CNKI), WanFang, and VIP Database. The search included publications from January 1, 2003, to March 31, 2023, with the last search done on Jan 15, 2023. Results We included 49 randomized controlled studies and retrospective cohort studies involving a total of 9,391 patients, with 4,841 in the UGHR and 4,550 in the FGAR. Specifically, UGHR exhibited a significantly shorter time to reduction (WMD = -4.183, 95% CI = (-5.402, -2.964), P < 0.001), a higher rate of successful reduction (RR = 1.128, 95% CI = (1.099, 1.157), P < 0.001), and a reduced length of hospital stay (WMD = -1.215, 95% CI = (-1.58, -0.85), P < 0.001). Furthermore, UGHR repositioning was associated with a diminished overall complication rate (RR = 0.296, 95% CI = (0.225, 0.389), P < 0.001) and a lowered incidence of perforation (RR = 0.405, 95% CI = (0.244, 0.670), P < 0.001). Conclusion UGHR offers the benefits of being non-radioactive, achieving a shorter reduction time, demonstrating a higher success rate in repositioning in particular, resulting in a reduced length of postoperative hospital stay, and yielding a lower overall incidence of postoperative complications, including a reduced risk of associated perforations.


Introductions
Intussusception stands as the most prevalent etiology of intestinal obstruction in pediatric patients.A substantial majority, approximately 75-90%, exhibit no identifiable cause and are classified as idiopathic intussusception [1][2][3][4].This condition primarily affects the small intestine, with infrequent occurrences in the large intestine [5].Clinical presentation typically encompasses symptoms such as abdominal pain, vomiting, and hematochezia, although the classic triad of symptoms is encountered in less than 25% of cases [6,7].Historically, fluoroscopy-guided air enema reduction (FGAR) has served as the primary therapeutic modality for intussusception.Its prominence stems from the demonstrated efficacy and safety of enema decompression established during the 1940s and 1950s.In recent years, ultrasound-guided hydrostatic enema reduction (UGHR) has gained traction as a non-invasive, radiation-free imaging technique [8][9][10].The advent of UGHR in clinical practice traces its origins back to 1982 when Kim et al. [11] first reported successful reduction of ileocolonic intussusception using warm saline enema under real-time ultrasound guidance.This approach has progressively gained popularity and involves ultrasound confirmation of the intussusception's location.A predetermined initial pressure is established, followed by ultrasound-guided injection of warm saline into the intestinal tract.Successful reduction is verified when saline flows into the intestinal tract from the ileocecal region, resulting in the manifestation of characteristic signs such as the "crab claw sign" and "honeycomb sign" [12].Although numerous studies have indicated that UGHR has advantages such as a higher success rate of resetting, greater safety, and radiation-free procedures, these merits are considered worthy of implementation in clinical practice.However, some studies also suggest that FGAR, as a traditional treatment method, remains practical in clinical settings due to its simplicity, ease of execution, and shorter learning curve.Besides, despite the burgeoning utilization of UGHR, a notable gap persists in terms of comprehensive, large-scale systematic comparisons and analyses assessing the efficacy, safety, and long-term prognostic implications of FGAR versus UGHR.We conducted a comprehensive meta-analysis comparing the efficacy and safety of air enema reduction and hydrostatic enema reduction for the treatment of childhood intussusception.Through an extensive literature search and rigorous clinical data analysis, our study aims to present a more secure and dependable therapeutic alternative for children with intussusception, thereby furnishing clinicians with compelling diagnostic and treatment evidence.

Methods
Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [13] (S1 Checklist).We registered the study on PROSPERO, of which the registration number was CRD42023414518.
We conducted a systematic review of studies published in PUBMED, Google Scholar, MEDLINE, Cochrane, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database.The search has a limit on date from Jan 1, 2003 to Mar 31, 2023, with the last search done on Jan 15, 2023.No publication restrictions or study design filters were applied.We formulated the search strategy, inclusion criteria and exclusion criteria according to the PICOS principles: (1) Type of study: randomized or non-randomized controlled trial, with the language limited to Chinese and English; (2) Participants of the study: pediatric patients (aged <18 years) who underwent enemas due to intussusception; (3) Interventions adopted: fluoroscopic air enema or ultrasound-guided saline enemas were used; (4) The main outcome indicators: time to reset, success rate of reset, recurrence rate, and occurrence of postoperative complications; (5)The search strategy for those databases was as follows: ((enema [Title/ Abstract]) AND (intussusceptions [Title/Abstract])), hydrostatic enema for intussusceptions, ((enema [Title/Abstract]) AND (intussusceptions [Title/Abstract])) AND (ultrasound [Title/ Abstract]), Reference lists from related articles were also scanned to broaden the search.A hand search was performed in all six databases.
Inclusion criteria were applied as follows: (1) confirmation of intussusception diagnosis; (2) subjects aged below 18 years; (3) availability of relevant outcome measures, such as patient numbers, study design, clinical symptomatology, reset success rates, complications, and recurrence; (4) provision of suitable statistical estimates or counts; and (5) comparative investigations involving both fluoroscopy-guided air enema reduction and ultrasound-guided hydrostatic enema reduction.
Exclusion criteria were applied as follows: (1) case reports involving fewer than five cases; (2) subjects exceeding 18 years of age; (3) articles categorized as reviews or meta-analyses; (4) conference abstracts; (5) articles with insufficient data; (6) cases included that did not pertain to acute intussusception or were combined with secondary intussusception; and (7) studies lacking a direct comparison between fluoroscopy-guided air enema reduction and ultrasoundguided hydrostatic enema reduction.
The following data were extracted: the first author's name, year of publication, study type, mean age, gender distribution, patient count, primary clinical symptoms, time required for reduction, reset pressure applied, reset success rate, duration of occult blood in stool, time until recovery of bowel function, length of hospital stay, recurrence rate, and complications.
The quality assessment of randomized controlled studies (RCTs) was conducted using the Cochrane Collaboration's Risk of Bias tool [14].Only studies with low or unclear risk of overall bias were included in the meta-analysis.Non-randomized studies underwent assessment with the Newcastle-Ottawa Scale (NOS) [15].The NOS score, ranging from 0 to 9 stars, evaluates studies across three categories: selection, comparability, and outcome/exposure.Studies with a NOS score of �6 stars were deemed high quality and incorporated into our analysis.The literature retrieval and data collection were to be carried out by at least two researchers.They independently read the titles and abstracts of the literature, excluding those that were not relevant to the content of this study.Subsequently, they will carefully read the full texts according to inclusion and exclusion criteria, extracting relevant information.In case of disagreements, resolution will be sought through negotiation, or a third researcher may be consulted for assistance in making a judgment.
Statistical analysis was conducted by STATA version 16.0 and RevMan version 5.2.Relative risk (RR) was applied for dichotomous variables, and weighted mean difference (WMD) was applied for continuous variables.Some study outcomes were reported as medians with ranges or mid-quartiles with ranges.According to the methods introduced by Luo et al. [16] and Wan et al. [17], those data were converted to means with deviations, thus the results for each group are presented as the mean ± standard deviation (x± s).The I 2 statistic was used to test the degrees of heterogeneity, the P-value of I 2 < 0.05 was used to indicate high heterogeneity and vice versa.The random-effects model was applied to pool the high heterogeneity results and the fixed-effects model was used for low heterogeneity (P-value of I 2 > 0.05; Table 2A and  2B).Begg's Test and Egger's Test were performed to assess the risk of bias (Table 3), while Begg's funnel plots were applied.P < 0.05 was considered to be statistically significant in the text.

Results
We initially identified 1231 articles through our comprehensive literature search.Prior to screening, 986 records were expunged from consideration.Subsequently, after the removal of duplicate entries, an additional 119 records were excluded following a meticulous full-text review, as they failed to satisfy our predefined inclusion criteria (Fig 1).Ultimately, our analysis encompassed a total of 49 studies mostly from the Asia and Europe, involving 9391 patients, with 4841 in the ultrasound-guided hydrostatic enema reduction group (UGHR) and 4550 in the fluoroscopy-guided air enema reduction group (FGAR).

Characteristics and risk of bias of included studies
The baseline characteristics of the 49 records, including first author, publication year, study type, number of patients, male/female sex ratio, and age of operation, are presented in Table 1.The NOS scores ranged from 6 to 8 stars, reflecting the quality of the non-randomized controlled studies (case-control and cohort studies) (S1
Clinical symptoms.Clinical symptoms reported in the studies primarily encompassed paroxysmal crying or abdominal pain, vomiting, the presence of an abdominal mass, and the passage of bloody stools.

Complications
To describe the occurrence of complications during the enema reduction procedure for intussusception, we calculated the overall complication rate, perforation rate, as well as rates of vomiting and diarrhea.

Publication bias
Begg's Test and Egger's Test were performed, and Begg's funnel plots were generated for some of the included records.Different subgroups were defined to assess publication bias (Table 3).Several largely symmetrical inverted funnel plots were observed (S8A-S8D Fig) , and publications displaying significant bias were removed.

Discussions
Pediatric intussusception is characterized by the invagination of one segment of the bowel into an immediately adjacent segment, resulting in the obstruction of intestinal contents.Over time, compromised vascular flow to the affected segment can lead to ischemia, necrosis, and potentially perforation [10,66].Therefore, early diagnosis and prompt treatment are imperative to improve prognosis.While radiological imaging plays a pivotal role in diagnosing and treating this condition, it is often not the initial choice in clinical practice due to concerns regarding radiation exposure.Ultrasound, conversely, stands out as the preferred imaging modality for diagnosis owing to its remarkable specificity (88%-100%), high sensitivity (98%-100%), and absence of ionizing radiation [67][68][69].In cases of uncomplicated pediatric intussusception, imaging-guided enema reduction stands as the globally recognized standard for nonsurgical treatment [70].To evaluate the efficacy and safety of ultrasound-guided hydrostatic enema reduction (UGHR) versus fluoroscopy-guided air enema reduction (FGAR), we conducted a comprehensive analysis encompassing clinical presentations, outcome parameters, and postoperative complications in both groups.Our primary objective is to equip healthcare practitioners with valuable insights for making informed treatment decisions when managing patients with intussusception.We enrolled a total of 49 studies into our analysis, of which was based on a mixture of randomized and non-randomized trials.The outcomes of the meta-analysis concerning clinical presentations of intussusception, including paroxysmal crying and abdominal pain, the presence of an abdominal mass, time of onset and the occurrence of blood in stools, consistently indicated no significant differences when comparing the two groups.
The findings of this meta-analysis indicate that UGHR is characterized by a shorter resetting time, a higher success rate of reset, and a reduced duration of hospitalization (Table 2A  and 2B).It has been proposed that during the UGHR procedure, real-time ultrasound enables the observation of the gradual movement of the intussusception towards the ileocecal region.During this phase, increasing the enema pressure can enhance the repositioning success rate and decrease the repositioning time.Additionally, the use of warm saline aids in the expulsion of intestinal contents, reducing the absorption of toxins by the intestinal tract.This, in turn, mitigates complications in children following the enema reduction, ultimately leading to a shorter hospital stay [12,36,41,62,71].
Complications arising from intussusception enema reduction are a critical aspect of assessing its safety, with intestinal perforation being one of the most severe complications [72].During air enema, when the intestinal lumen pressure is high, the intestinal tube undergoes significant expansion.If excessive or sudden pressure is applied, air entering the terminal ileum may result in a tense pneumoperitoneum, potentially leading to intestinal perforation [73].It has been reported [74] that UGHR may be less hygienic and could lead to intra-abdominal fecal contamination in case of intestinal perforation, which, if not promptly treated, can result in severe complications and endanger the patient's life.The meta-analysis presented in this article demonstrates that UGHR repositioning is associated with a lower overall complication rate, including a lower incidence of perforation (Table 2A).Furthermore, the occurrence of postoperative vomiting and diarrhea is significantly reduced in children.Pan et al [36] suggest that this reduction in complications may be attributed to the slower movement of the water column during the water enema, causing less damage to the intestinal mucosa and possessing some mucosal dialysis function, resulting in a lower incidence of postoperative complications.Additionally, UGHR enables the measurement of intestinal tube hemodynamics, observation of the intestinal wall's blood supply, and determination of its viability.This can effectively mitigate the risk of perforation due to high pressure during the enema procedure [41,63].It is recommended to employ intermittent ultrasound monitoring to assess the intestinal canal diameter during enema operations, reducing the likelihood of perforation.UGHR also allows for clear visualization of the intussusception mass and early detection of pathological predisposing points or residual intussusception.Overall, it can be inferred that UGHR provides significant advantages in the treatment of intussusception in children.
However, the main disadvantage of UGHR is that the success of its enemas is significantly related to the experience of the operator, which requires pediatric surgeons to be taught and trained in ultrasound or radiology.This study exhibits several limitations too.Firstly, it's worth noting that most studies included in this analysis were single-center trials.While our overall sample size is substantial, single-center studies may induce inevitable biases.Secondly, it's noteworthy that the surgical team was also involved in authoring the reports.This potential author-surgeon bias should be taken into consideration when interpreting the findings.Thirdly, certain outcome measures, such as repositioning pressure, duration of postoperative blood in the stool, and postoperative vomiting or diarrhea, exhibited lower reliability due to a limited number of reported studies, resulting in a relatively small sample size for these specific parameters.Lastly, the enrolled studies were mostly from the Asia and Europe, an inevitable selection bias was existed.

Conclusions
In conclusion, it can be affirmed that both UGHR and FGAR represent safe and effective nonsurgical approaches for the management of pediatric acute intussusception.However, when comparing the two methods, UGHR emerges as the preferable choice.This preference is rooted in its nonradioactive nature, quicker repositioning times, higher success rates in repositioning, reduced postoperative hospitalization durations, fewer overall postoperative complications, and a notably decreased incidence of concurrent perforation when compared to FGAR.

Fig 1 .
Fig 1. Flow diagram representing the selection of study.https://doi.org/10.1371/journal.pone.0297985.g001 Table), and S1A and S1B Fig presents the Cochrane Collaboration's Risk of Bias Tool for the randomized controlled studies (RCTs) that were judged to have a low risk of bias.Table 2(A) and 2(B) show the overall analyses for dichotomous and continuous variables, respectively.

Table 1 . Baseline characteristics of 49 records with 9391 patients enrolled in the meta-analysis.
Outcomes.The primary outcome measures for enema reduction in cases of intussusception comprise resetting time, resetting pressure, success rate of reduction, duration of occult blood in stool, length of hospitalization, and recurrence.Resetting time: Thirty-one studies contributed data about UGHR and FGAR, including 4236 patients (2146 in the UGHR and 2090 in the FGAR, Table 2(B)).Random-effects model

Table 3 . Begg's and Egger's test of publication bias of clinical characteristics.
a : P value means the value of Pr>|z| (continuity corrected, in Begg's Test) or P>|t| (in Egger's Test) * :P value < 0.05 was considered to have a high risk of publication bias.https://doi.org/10.1371/journal.pone.0297985.t003